Genetic variants reduce risk of Alzheimer's disease

February 04, 2020

A DNA study of over 10,000 people by UCL scientists has identified a class of gene variants that appear to protect against Alzheimer's disease.

The findings, published in Annals of Human Genetics, suggest these naturally occurring gene variants reduce the functioning of proteins called tyrosine phosphatases, which are known to impair the activity of a cell signalling pathway known as PI3K/Akt/GSK-3β. This pathway is important for cell survival.

The research builds on previous studies in mice and rats, which suggested inhibiting the function of these proteins might be protective against Alzheimer's disease, but this is the first time such an effect has been demonstrated in people.

Researchers believe the PI3K/Akt/GSK-3β signalling pathway could be a key target for therapeutic drugs and the findings also strengthen evidence that other genes could be linked to either elevated or reduced risk of Alzheimer's disease.

"These results are quite encouraging. It looks as though when naturally-occurring genetic variants reduce the activity of tyrosine phosphatases then this makes Alzheimer's disease less likely to develop, suggesting that drugs which have the same effect might also be protective," said the study's lead author, Professor David Curtis (UCL Genetics Institute).

In this study, scientists analysed DNA from 10,000 people: half with Alzheimer's disease and half without.

In total, researchers examined all DNA sequence variants in over 15,000 genes, including over one million individual variants, in order to identify genes in which damaging variants were more common in people with or without Alzheimer's disease.

Researchers found that Alzheimer's disease risk is lower in people with damaging variants in a particular class of genes, which code for tyrosine phosphatases. The researchers say the findings suggest that drugs which have the same effect might also be able to reduce the risk of Alzheimer's. Professor Curtis points out there are already some drugs which act on tyrosine phosphatases but they have not yet been tested in clinical trials.

"Here's a natural experiment in people that helps us understand how Alzheimer's disease develops: as some people have these genetic variants and some don't, we can see that the impact of having particular variants is a reduced likelihood of developing Alzheimer's disease," Professor Curtis added.

The researchers also found suggestive evidence that if there are genetic variants which damage the gene for the PI3K protein, then the risk of Alzheimer's increases.

"There is a consistent story in our results that the activity of the PI3K/Akt/GSK-3β signalling pathway is protective, which is exactly in line with findings from animal studies," said Professor Curtis.

The study also found suggestive evidence to implicate a gene not previously known to affect Alzheimer's risk, called C1R. The gene is known to affect periodontal Ehlers-Danlos syndrome, a disease involving chronic gum inflammation. Some previous research suggests that gum infections may increase the risk of Alzheimer's disease, so Professor Curtis speculates there may be a mechanism whereby genetic variants in C1R lead to some degree of gum disease, which in turn predisposes to Alzheimer's disease.

This study builds on a major 2019 study involving UCL researchers that identified five new risk genes for Alzheimer's disease, adding to UCL's record of world-leading research in dementia and genetics.

"Finding DNA variants which modify the risk of Alzheimer's disease is useful as it may help us develop drugs which target the same proteins. Simultaneously, researchers at UCL and across the globe are finding ways to detect the earliest stages of Alzheimer's disease, before it causes any problems. As our understanding improves, there may be opportunities to intervene with treatments to prevent the disease from progressing," Professor Curtis said.

Professor Curtis, honorary professor at the UCL Genetics Institute and at Queen Mary University London, conducted the study with a team of undergraduate students in the UCL Genetics Institute. The data was generated by an international collaboration, the Alzheimer's Disease Sequencing Project.
-end-


University College London

Related Genetics Articles from Brightsurf:

Human genetics: A look in the mirror
Genome Biology and Evolution's latest virtual issue highlights recent research published in the journal within the field of human genetics.

The genetics of blood: A global perspective
To better understand the properties of blood cells, an international team led by UdeM's Guillaume Lettre has been examining variations in the DNA of 746,667 people worldwide.

Turning to genetics to treat little hearts
Researchers makes a breakthrough in understanding the mechanisms of a common congenital heart disease.

New drugs more likely to be approved if backed up by genetics
A new drug candidate is more likely to be approved for use if it targets a gene known to be linked to the disease; a finding that can help pharmaceutical companies to focus their drug development efforts.

Mapping millet genetics
New DNA sequences will aid in the development of improved millet varieties

Genetics to feed the world
A study, published in Nature Genetics, demonstrated the effectiveness of the technology known as genomic selection in a wheat improvement program.

The genetics of cancer
A research team has identified a new circular RNA (ribonucleic acid) that increases tumor activity in soft tissue and connective tissue tumors.

New results on fungal genetics
An international team of researchers has found unusual genetic features in fungi of the order Trichosporonales.

Mouse genetics influences the microbiome more than environment
Genetics has a greater impact on the microbiome than maternal birth environment, at least in mice, according to a study published this week in Applied and Environmental Microbiology.

New insights into genetics of fly longevity
Alexey Moskalev, Ph.D., Head of the Laboratory of Molecular Radiobiology and Gerontology Institute of Biology, and co-authors from the Institute of biology of Komi Science Center of RAS, Engelgard's Institute of molecular biology, involved in the study of the aging mechanisms and longevity of model animals announce the publication of a scientific article titled: 'The Neuronal Overexpression of Gclc in Drosophila melanogaster Induces Life Extension With Longevity-Associated Transcriptomic Changes in the Thorax' in Frontiers in Genetics - a leading open science platform.

Read More: Genetics News and Genetics Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.